Organ systems such as heart, muscle and nerve derive their essential excitability due to the presence of voltage-dependent, cation-selective channels in their cell membranes. The objective of this research proposal is to develop an understanding of the principles of polypeptide and protein transmembrane channel conductance with emphasis or molecular conformation, voltage dependence, kinetics and ion selectivity which are central to a full understanding of electrophysiology. The approach is to utilize derivatives and analogues of the two known monovalent cation selective channels (gramicidin A and HCO-(L-Ala-L-Ala-Gly)5-OMe and to employ a battery of spectroscopic methods. Theoretical conformational energy calculations, peptide syntheses and model lipid membranes in order to extend our knowledge of the molecular structures and mechanisms of cation vs anion selectivity, of monovalent vs divalent cation selectivity and of voltage dependent selective conductance (gating) and to achieve molecular structures and mechanisms for greater selectivity among monovalent cations and for increased voltage dependence of the gating process. Recognizing that the excitability of cell membranes and its consequences are fundamental to the definition of living systems and that the loss of the resulting electrical signals from the heart and brain are utilized in the definition of death, the development of the principles underlying the excitability of cell membranes achieves a certain prominence and the search for the molecular structures and mechanisms a certain sense of significance.